Discussion
To our knowledge, our study is the largest, multicenter, prospective
study of CRRT conducted in critically ill children with SHLH-associated
MODS. Furthermore, we additionally reported the first data on detailing
the PICU course and outcome of these patients. We observed that patients
with SHLH and MODS received CRRT in PICU was associated with a high PICU
mortality at 46.2% (22/52). Our data also demonstrated that the number
of organ dysfunction and serum IL-6 level at CRRT initiation higher than
3 and 13.12pg/ml are independent risk factors of initial PICU mortality.
The overall mortality rate from HLH ranges across studies from 22 to
59%[12]. In recent years, a trend to a reduction in
mortality
among critically ill patients
with
SHLH admitted to the ICU was
observed. In the sub-group of
pediatric
patients, the same trend was also found. In 2018, Gregory and colleagues
described a single center experience of HLH in a PICU over a 10-year
period, which including 42 patients, overall initial PICU
hospitalization mortality and 1-year mortality was 21% and 42%
respectively[13].
This outcome benefits may be owed to improvement in
chemotherapy, multiple organ support technology and better intensive
care management. Nevertheless, there is no published literature
reporting mortality in SHLH-associated MODS patients required CRRT. In
our registry, total
initial
PICU hospitalization mortality for our patient cohort was 46.2%
(22/52). This may shed light onto the quite poor outcomes among patients
with SHLH and MODS who need CRRT. Thus, the development of therapies
targeted at preventing or limiting the progress of MODS is urgently
needed.
MODS is the leading cause of hospital death in SHLH patients and the
prognosis depends mainly on the number and severity of organ
dysfunctions. Numerous studies reported over half of deaths occur within
30 days after SHLH diagnosis due to MODS or second infection[14,15].
Leow et al[16], assessed poor prognostic factors and mortality for
pediatric patients with HLH admitted to the cardiac ICU, they found
patients with a higher mortality index score at admission, higher serum
lactate levels, the need for mechanical ventilation, vasoactives and
CRRT were associated with higher mortality. Indeed, we demonstrated a
correlation between the number of organ dysfunctions and mortality.
Significantly, nonsurvivors had more respiratory, cardiovascular and
gastrointestinal dysfunctions. Likewise, the use of organ support
(mechanical ventilation, vasoactive agents) was also higher in the
nonsurvivors.
Abrupt onset of rapid progress to MODS is common in fatal HLH
patients[17] MODS is often reported at the advanced stage of SHLH
and is related to abnormally higher concentrations of hypercytokinemia
including interferon-γ(IFN-γ), tumoral necrosis factor-α (TNF-α),
interleukin-10 (IL- 10), IL-6 and so on[18]. IL-6 amplifies
TLR-induced inflammatory response also in cells originating from
inflammatory site. In vitro, Claudia et al. demonstrated that, prolonged
exposure of human macrophages to IL-6 leads to increased production of
cytokines, including (C-X-C Motif) Ligand 8 (CXCL-8) and Tumor Necrosis
Factor-α (TNF-α)[19]. A single-center study reported, renal failure
was related to abnormally high concentrations of nephrotoxic
interleukin-6 (IL-6) in serum[20]. Our data demonstrated that serum
IL-6 levels was positively associated with the number of dysfunction
organs on correlational analysis which corroborated similar findings
from previous studies.
The prognostic significance of cytokines for early death has once been
reported[21]. Tang et al[22] found high
IFN-γ and IL-10 levels were
associated with early death. It is worth noting that, in our study serum
IL-6 levels at PICU admission was higher in the non-survivor group than
survivor group. We further found that highly elevated IL-6 level
(>13.12pg/mL)
was an independent risk factor of hospital death in critically
SHLH-associated MODS pediatric patients. This result was consistent with
previous study of HLH, which showed patients in the non-survivors group
had higher IL-6, IFN-γ and IL-10 levels[23]. IL-6 levels are usually
significantly elevated in patients with sepsis, which is considered to
be the major cause of mobility and mortality in pediatric SHLH
patients[24]. This may partially explain the phenomenon of higher
level of IL-6 in SHLH patients with death. As a result, it may be
reasonable to consider IL-6 levels greater than13.12 pg/ml as a
prognostic factor maker of SHLH.
Current management of SHLH-associated MODS includes prompt clinical
stabilization with ICU-level organ supportive care, applying specific
measures to control the hyperinflammation, identification and treatment
of the underlying cause of SHLH and infectious complications. From the
onset, aggressive interventions for the treatment of multiorgan
dysfunction are usually conducted to stabilize the patient’s status
while allowing time for other therapeutic strategy to treat SHLH.
Management of the hyperinflammatory response focuses on blocking
excessive cytokine production and eliminating the triggers are also
important[14,25]. Medications, such as
corticosteroids
and immunosuppressants, are recommended in SHLH treatment to suppress
the inflammatory response and control cell proliferation[9,26].
However, corticosteroids and immunosuppression leave many SHLH patients
susceptible to infection, as well as secondary infections can trigger
reactivation of the underlying hyperinflammatory response leading to
additional morbidity and mortality.
CRRT as a new type of renal replacement, is being used more often in
critically ill children with MODS. CRRT has been also recommended as an
effective therapeutic for the treatment of systemic inflammatory
syndromes. With regard to severe sepsis adjunctive therapies,
inflammatory mediator modulation can be achieved through
hemofiltration (HF) based CRRT
mode, such as continuous venovenous hemofiltration (CVVH) or continuous
venovenous hemodiafiltration (CVVHDF). One of the mechanisms for the
beneficial effect of HF in sepsis may be the convective clearance of
soluble inflammatory mediators. Over the last few years, animal
experiments and human studies have shown that, CVVH/CVVHDF can remove
soluble inflammatory mediators of sepsis, as well as attenuate the
severity of the response to sepsis. DiCarlo et al[27] demonstrated
the utility of continuous hemofiltration in attenuating the consequences
of excess cytokine activity and the degree of lactate in three HLH
patients with MODS. Our previous single-center nonrandomized concurrent
control trial showed high-volume hemofiltration (HVHF) may be an
effective adjunctive treatment in SHLH/MAS by improving organ function
and decreasing serum level of TNF-α and IL-6[8]. There are several
small reports of treatment of SHLH with alternative therapeutics
directed against IL-1, IL-6 and TNF-α in serum, which have demonstrated
clinical benefits for these patients[28].
Our study has some limitations. First, gene sequencing was not performed
in all patients, so that the proportion of FHL remained uncertain.
Second, although this study was based on a multi-centered prospective
study, relatively small number of patients was warranted to validate the
results.